Adenylyl cyclase (AC) has long been recognized as a pivotal effector molecule in cardiac myocytes and other[unreadable] cells. In 1998 we showed that the amount of adenylyl cyclase sets a limit on the ability of cardiac myocytes[unreadable] to generate cAMP. Subsequent studies showed that AC gene expression has a pronounced favorable effect[unreadable] on cardiovascular function in normal and failing hearts, including increased global left ventricular (LV)[unreadable] function, increased survival and prevention of deleterious remodeling. Data from our laboratory indicate[unreadable] that AC expression also is associated with reduced mortality in acute myocardial infarction.[unreadable] We propose a clinical trial of intracoronary delivery of an adenovirus encoding adenylyl cyclase type[unreadable] VI (ACVI) in patients with congestive heart failure (CHF). These studies stem from extensive preclinical data[unreadable] that we have obtained during the initial four years of the current Program (now submitted for renewal). We[unreadable] expect to be treating patients in Year 5 of the current Program, having achieved all but the final regulatory[unreadable] milestones. We project that this first trial will be complete in Year 3 of the proposed Program. Performing[unreadable] vector development and preclinical studies in parallel with the clinical study will enable a seamless[unreadable] transition to the conduct of a Phase 2 study using a regulated expression vector during the five year tenure[unreadable] of the proposed renewal award.[unreadable] I.B. Hypothesis. Intracoronary delivery of an adenovirus encoding ACVI will improve heart[unreadable] function and reduce symptoms in patients with Class III/IV congestive heart[unreadable] failure.[unreadable] Specific Aim 1. To determine the safety and potential efficacy of intracoronary delivery of an[unreadable] adenovirus encoding ACVI in patients with Class III/IV heart failure in a Phase 1/Phase 2 clinical trial.[unreadable] Specific Aim 2. To determine the safety and efficacy of intracoronary delivery of an adenovirus[unreadable] encoding ACVI (with regulated expression) in patients with Class III/IV heart[unreadable] failure in a Phase 2 clinical trial.[unreadable]